Depression is a common co-morbidity and an independent risk factor for hospitalization and death in Chronic Kidney Disease (CKD) patients on chronic dialysis. Our preliminary data revealed that 21% of Veterans with predialysis CKD suffer from a major depressive episode (MDE) and that, independent of co-morbidities, those with a MDE are 2 times more likely to be hospitalized, initiate dialysis or die within a year as compared to those without a MDE. However, only a minority of CKD patients with depression are treated with antidepressants. Reasons for low treatment rates include a lack of published data that clearly support or refute efficacy and safety of antidepressants in CKD patients. The Sertraline AntiDepressant Heart Attack Randomized Trial showed benefit of serotonin-selective reuptake inhibitor (SSRI) sertraline on cardiovascular outcomes but excluded patients with moderate to severe CKD. Given the excessive rates of cardiovascular (CV) death in CKD patients and the correlation of depression with increased CV events, it becomes imperative to not only investigate whether treatment of depression is safe and efficacious in these patients, but also whether it would result in a reduction in CV mortality. In addition, prior research has shown that deployment stressors and exposure to combat result in considerable risks of mental health problems such as major depression particularly in Veterans, which results in impairment in social functioning and in the ability to work. Mental health problems also lead to increased utilization of health care services and, therefore, health care-related costs among Veterans. We hypothesize that short-term treatment of a MDE with sertraline will improve depression symptom severity and quality of life in patients with predialysis stages 3-5 CKD. We further hypothesize that treatment of MDE with sertraline will not result in more serious adverse events than treatment with placebo in these patients. The specific objectives of this study are to 1) determine if treatment with sertraline, as compared with placebo, results in an improvement in depression symptom severity in a randomized, double-blinded, placebo-controlled flexible-dose 12-week trial involving 200 Veterans with predialysis stages 3-5 CKD;2) determine if sertraline treatment improves overall function and quality of life as assessed by the Work and Social Adjustment Scale and the Short Form 12 scores, respectively;and 3) determine if sertraline, as compared with placebo, will result in more serious adverse events including bleeding requiring blood transfusion or hospitalization. The readily available patient population and the application of our proven methodology for measuring depression is a powerful combination that will help provide urgently needed data on the efficacy and safety of a typical SSRI in CKD patients. These data can be used to power a future multi-center large-scale trial designed to determine whether treatment of depression improves morbidity, mortality and quality of life in patients with CKD. PUBLIC HEALTH RELEVANCE: The relevance to Veteran's health is providing urgently needed data on the efficacy and safety of a typical serotonin-selective reuptake inhibitor in Chronic Kidney Disease patients that can be used to power a future multi-center large-scale trial, such as a Veterans Affairs Cooperative Study, designed to determine whether treatment of depression improves morbidity, mortality and quality of life, as well as lessens health care services utilization, in these patients. This becomes particularly important to the Veteran patient population that has a higher prevalence of both depression and medical co-morbidities such as Chronic Kidney Disease.